Human leukocyte antigen (HLA) class II histocompatibility antigen gamma chain, also called HLA-DR antigen-associated invariant chain, Ia antigen-associated invariant chain, Ii and CD74, is a transmembrane protein with a short cytoplasmic tail. The primary function of CD74 is to regulate peptide loading onto the major histocompatibility complex (MHC) class II heterodimers in intracellular compartments.
Only a small portion of the total cell CD74 content is expressed on the cell surface. Cell surface CD74 is very rapidly internalized both with and without CD74 antibodies bound (Roche P A et al., PNAS 1993; 90: 8581-8585; Hansen H J et al., Biochem J 1996; 320: 293-300; Ong G L et al., Immunology 1999; 98:296-302). The steady-state level of cell surface CD74 is therefore rather low, varying in monocytes from a few hundred to a few thousand molecules per cell.
The exact function of cell surface-expressed CD74 is not known, but studies have documented CD74 as a membrane receptor for the pro-inflammatory cytokine macrophage migration inhibitory factor (MIF). MIF binding to CD74 activates downstream signaling through the MAPK and Akt pathways and promotes cell proliferation and survival. This interaction is likely regulated also by the presence of CD44, CXCR2 or CXCR4 as co-receptors.
Upregulation of CD74 expression has been observed in many types of cancer, as well as in certain infections and inflammatory conditions. Various formats of a humanized CD74-specific monoclonal antibody, hLL1, have been proposed for treatment of CD74-positive tumors (Chang C H et al., Blood 2005;106:4308-4314; Sapra P et al., Clin Can Res 2005;11:5257-5264; Stein R et al., Blood 2004;104:3705-11; Govindan S V et al. J Nucl Med 2000;41:2089-2097; Hertlein E et al., Blood 2010; 116: 2554-2558; Stein R et al., Clin Cancer Res 2009; 15: 2808-2817; Sharkey R M et al., J Nucl Med 2009; 50: 444-453; Lundberg B B et al., Drug Deliv 2007; 14: 171-175; Griffiths G L et al., Int J Cancer 1999; 81: 985-992; Griffiths G L et al., Cancer Res 2003; 9: 6567-6571; Ochakovskaya R et al., Clin Cancer Res 2001; 7: 1505-1510; Shih L et al., Cancer Immunol Immunother; Burton J D et al., Clin Cancer Res 2004; 10: 6606-6611; Lundberg B B et al., J Control Release 2004; 94: 155-161).
Although much progress has been made, there remains a need for improved methods of treating serious diseases, e.g. improved treatment of cancer, based on therapeutic antibodies and ADCs.